[unreadable] Depression is a stress-related heterogeneous disorder. The mechanisms underlying the pathogenesis of depression and the therapeutic actions of antidepressant treatments are as yet not well understood. Understanding the factors that contribute to the generation of individual differences in vulnerability to depressive disorders is of critical importance. One hypothesis is that early life events result in persistent alterations in the nervous system thus contributing to the programming of individual differences in vulnerability to adult psychopathology. The specific pathways that are influenced by early life events and their role in setting up individual differences in adult vulnerability is not as yet clearly characterized. The cyclic AMP cascade, the transcription factor cAMP response element binding protein (CREB), and the neurotrophin, Brain derived neurotrophic factor (BDNF) have been implicated in the pathophysiology and treatment of depression. The role of the cAMP-CREB cascade and the neurotrophin BDNF in the effects of early-life events is relatively unexplored. The influence of early life events, namely maternal separation and postnatal handling in rodent models, on CREB and BDNF and the role of the cAMP-CREB cascade and BDNF in contributing to the actions of early life events are the main thrust of this collaborative FIRCA project. Approaches used to address the role of these molecules will capitalize on the use of pharmacological agents, viral expression of molecules and transgenic/deletion mouse mutants. We will ask whether regulation of these molecules influences the effects of maternal separation and postnatal handling on (1) gene expression (2) hippocampal progenitor proliferation (3) apoptosis in the hippocampus and (4) behavioral models such as forced swim test and open-field test. The above studies will provide insights into whether the cAMP-CREB cascade and BDNF are sensitive to early-life events and will address whether alterations in these pathways contribute to the generation of individual differences in neural systems thus providing a substrate for altered vulnerability to stress-related disorders such as depression. The proposed project will be executed in collaboration with Dr. Vidita Vaidya at TIFR, India and the research is an extension of the parent NIH grant # RO1 MH45481. [unreadable] [unreadable]